One of the most well-known and widely-used class of antibacterial agents is the beta-lactam antibiotics. These compounds are characterized by a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (pencillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. In many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components. A variety of compounds have been reported to possess beta-lactamase inhibitory activity, including clavulanic acid and other fermentation-derived compounds [Brown et al., J. Antibiot. 29, 668 (1976)]as well as compounds derived from beta-lactam antibiotics by partial synthesis [see for example English et al., Antimicrobial Agents and Chemotherapy 14, 414 (1978)].
6-Beta-hydroxypenicillanic acid (employed as starting material in the present synthesis), its benzyl ester, as well as various acylated derivatives thereof, including phenoxyacetyl, phenylacetyl, benzenesulfonyl and methanesulfonyl, have been previously disclosed [Sheehan and Lo, U.S. Pat. No, 4,143,046; see also Lo and Sheehan, J. Am. Chem. Soc. 94, 8253 (1972)]. Sheehan and Lo do not report these compounds to possess activity as beta-lactamase inhibitors.